This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The nervous system was once considered to be "immune privileged" and isolated from immune system activity. However, a preponderance of evidence indicates that proper development and function of the central nervous system (CNS) relies on regulated interactions between nervous system and immune cells. Microglia are the resident immune cells of the CNS and respond rapidly to changes in the CNS environment. Microglia exhibit phagocytic activity following neuronal damage. Activated microglia produce neurotoxic molecules including inflammatory cytokines, chemokines, arachidonic acid, reactive oxygen and nitrogen species, and growth inhibiting proteins such as prostaglandins (Kim and Vellis, 2005;Lai and Todd, 2006). Conversely, emerging evidence suggests that, given specific activator(s), microglia may function to support neuronal survival, differentiation and potentially regeneration. Both in vitro and in vivo studies have shown that microglia produce neurotrophic factors such as nerve growth factor (NGF), neurotrophin 3 (NT3), and brain-derived neurotrophic factor (BDNF) (Kim and de Vellis, 2005;Morgan et al., 2004). Additional experiments have demonstrated that co-cultures of neurons and microglia increase neurogenesis in neural progenitor cells (Walton et al., 2006). Little is known about whether activated microglia are capable of producing neurotrophic effects in damaged neurons and which signaling and epigenetic mechanisms underlie these processes. Previous experiments have suggested that the PI3K/AKT and MAPK pathways could act as potential signaling mechanisms and it is likely that regulation of microglial signaling pathways determine their neurotrophic or neurotoxic phenotype. To investigate the signaling mechanisms and gene regulation involved in the immune response to neuronal damage, this proposal presents an in vitro model system employing state-of-the-art technology that is readily accessible to and utilized by undergraduate research students. Increasing our understanding of the mechanisms that drive neurotrophic verses neurotoxic phenotypes in microglia will provide insight into the intrinsic neuroprotective role of immune activity in the CNS and may aid in the development of methodologies to promote such activity during neurodegenerative disease or regeneration following injury.